Pseudomonas aeruginosa (Pa) is a major cause of pneumonia in immunocompromised and hospitalized patients. The morbidity and mortality of Pa respiratory infections usually involves extension of Pa to the alveolar space and the development of pneumonia. The alveolar epithelium is the largest surface area exposed to the external environment and consists of 95% type I pneumocytes. We have recently shown that Pa invades type I pneumocytes by co-opting lipid raft mediated endocytic pathways during the pathogenesis of Pa pneumonia. Invasion of type I pneumocytes may protect Pa from phagocytosis by alveolar macrophages and offer a protected environment for replication. In addition, invasion of type I cells may facilitate dissemination across the alveolar capillary barrier. We have also shown that Pa invasion of alveolar epithelial cells is dependent on the expression and tyrosine phosphorylation of caveolin-2. Caveolin proteins are key components of lipid rafts and caveolae. In addition to serving as key structural proteins that organize caveolae platforms, caveolin proteins are important in regulating endocytosis and cell signaling. Caveolin-1 and 2 are co-expressed on a wide range of cell types and are particularly abundant in type I pneumocytes. Caveolin-1 has been implicated as a critical mediator of endocytosis and cell signaling. While caveolin-1 has been extensively studied, very little is known about the function of caveolin-2. Studies with caveolin-2 deficient mice suggest that caveolin-2 plays a critical role in cell signaling as well as lung growth and development. Hypothesis: The caveolin-2 signaling pathway controls the ability of Pa to invade the alveolar epithelium via lipid raft mediated endocytosis. Caveolin deficient mice will be resistant to Pa pulmonary infections as a result of impaired bacterial invasion of the alveolar epithelium. Relevance: Despite antibiotic therapy Pseudomonas pneumonia continues to be a major cause of morbidity and mortality in immunocompromised patients, hospitalized patients as well as patients with cystic fibrosis. This research will provide a better understanding of the pathogenesis of Pseudomonas pneumonia and specifically the interactions between the bacterial pathogen and host epithelial cells. A better understanding of these events is required for the eventual development of new adjunctive therapiesand possible prophylactic strategies for high risk patients.